Development of effective human immunodeficiency virus (HIV) vaccines is one of the primary goals of current acquired immunodeficiency syndrome (AIDS) research. Despite progress in prevention and powerful drug combinations to treat HIV infection, an estimated 16,000 people become infected every day. Over 90% of new infections occur in developing countries for which the recent medical advances are not immediately applicable or affordable. The best hope for these countries is the development of an effective, accessible HIV vaccine. There is now growing optimism among scientists that an AIDS vaccine may be possible (McMichael & Hanke 1999 Nat. Med. 5, 612-614; Gold 1999 IAVI Report 4, pp 1-2, 8-9, 15-16 & 18).
An ideal prophylactic vaccine should induce sterilizing immunity, so that after exposure, the virus would never be detected in the body. However, this is probably an unrealistic objective. Rather, an attainable goal may be a vaccine-induced immunity that results in a limited and transient virus replication, after which the virus becomes undetectable, there are no signs of disease and no transmission to other individuals. Alternatively, a potentially successful vaccine may induce immune responses that at least hold the virus in check at levels so low, that both progression to AIDS and transmission are entirely or substantially prevented.
To induce sterilizing immunity, a prophylactic vaccine may need to elicit both humoral and cell-mediated immune responses. Since HIV was isolated and sequenced, there has been a considerable effort to develop envelope-based vaccines inducing neutralizing antibodies (nAb). However, this has proved to be exceedingly difficult (Heilman & Baltimore 1998 Nat. Med. 4 (4 Suppl.) 532-534). Although some success was reported in inducing nAb against laboratory HIV strains (Berman et al, 1990 Nature 345, 622-625; Fultz et al, 1992 Science 256, 1687-1690), it has been extremely difficult to neutralize primary isolates (Trkola et al, 1998 J. Virol. 72, 1876-1885; Haynes 1996 Lancet 34, 933-937). An explanation for the first 15 years of relative failure has been provided by the crystal structure of the core gp 120, which revealed multiple mechanisms by which HIV prevents efficient induction of nAb (Wyatt et al, 1998 Nature 393, 705-711; Kwong et al, 1998 Nature 393, 638-659). As a result of these difficulties, the emphasis of many vaccine designers has shifted to the induction of cell-mediated immune responses, which are mediated (predominantly) by cytotoxic T lymphocytes.
Cytotoxic T lymphocytes (CTL) are usually CD8+ cells and participate in an organism's defence in at least two different ways: they kill virus-infected cells; and they secrete a variety of cytokines and chemokines that directly or indirectly contribute to the suppression of virus replication. CTL-mediated protection after vaccination may depend on the levels of CTL present in the circulation and, perhaps, specifically for proteins expressed early (regulatory proteins) rather than late (structural proteins) in the replication cycle.
The induction and maintenance of CD8+ T cell responses require “help” provided by CD4+ T lymphocytes (helper T cells). In some HIV-infected individuals, high levels of HIV-specific helper response have been detected.
Identification of methods for induction of strong CD8+ T cell responses would provide tools for studying their role(s) in shaping the course of HIV infection and may stimulate progress towards an effective HIV vaccine. Previously, a prototype HIV vaccine was constructed as a string of partially overlapping epitopes recognised by murine, macaque and human CTL, which was delivered by vaccine vehicles that were safe and acceptable for use in humans, a DNA vector and modified vaccinia virus Ankara (MVA) vector (Hanke et al, 1998 Vaccine 16, 426-435; Hanke et al, 1998 J. Gen. Virol. 79, 83-90). In mice, the most potent protocol for induction of CTL was found to be DNA priming followed by MVA boosting (Hanke et al, 1998 Vaccine 16, 439-445; Schneider et al, 1998 Nat. Med. 4, 397-402) that is, priming mice with nucleic acid encoding the relevant polypeptide, followed by boosting the mice by inoculation with a modified vaccinia virus Ankara (“MVA”) vector expressing the relevant epitopes.
WO 98/56919 discloses a “prime-boost” vaccination strategy, involving (i) priming with a composition comprising a source of one or more T cell epitopes of a target antigen, together with a pharmaceutically acceptable carrier, and (ii) boosting with a composition comprising a source of one or more T cell epitopes of the target antigen, including at least one T cell epitope that is the same as a T cell epitope of the priming composition.
The present invention aims, inter alia, to provide immunogens which may be useful in eliciting an HIV-specific response in humans. All documents and publications mentioned in this specification are incorporated herein by reference.